The capacity to work is reduced in elderly persons. The contribution of changes in skeletal muscle microcirculation to this age-related decline in physiological function remains to be elucidated. The increase in skeletal muscle blood flow that accompanies muscle contraction (functional hyperemia) is impaired in aged male rats but is unaltered in aged female rats. The inability of muscle to regulate its own blood flow to meet metabolic demand may result in ischemia and impaired physical function in elderly persons, especially men. The overall goal of this proposal is to investigate mechanisms responsible for the impaired functional hyperemia associated with aging and to evaluate the apparent protective mechanisms in females. The progressive decline in physiological function with age has been largely attributed to oxidative stress (the "free-radical theory of aging"). We have previously shown that in younger animals, functional hyperemia is mediated largely by a vasodilatory metabolite of cyclooxygenase (probably prostacyclin) released from venular endothelium. Thus, it is hypothesized that the impaired hyperemic response to skeletal muscle contraction in aged male rats is due to a reduced availability of prostacyclin due to oxidative stress. Specific aim 1 will evaluate the contribution of prostacyclin to functional hyperemia of aged male and female rats in vivo. Prostacylin release from small veins will also be examined. Specific aim 2 will test the hypothesis that oxidative stress is increased in skeletal muscle of aged male animals. Levels of factors known to be activated by oxidative stress (superoxide, F2-isoprostanes, TBARS, peroxynitrite) will be measure in samples of skeletal muscle from male and female rats of various ages. Specific aim 3 will test the hypothesis that inhibition of oxidative stress, using chronic antioxidant therapy, will prevent the impaired hyperemic response to muscle contraction in aged male rats. Two therapeutic regimes will be used for these studies to determine whether antioxidant therapy is of use once oxidative stress has already developed or whether treatment must be commenced at a young age and thus act as a prophylactic. The data generated from this proposal will enhance our knowledge of changes in skeletal muscle microcirculation function with aging and will broaden our understanding of gender difference in cardiovascular function.